Despite advances in immunosuppression, long-term allograft survival remains sub-optimal due to unabated chronic rejection that causes relentless graft attrition. B cells and memory T cells contribute to chronic rejection of transplanted organs. Current immunosuppressive regimens inhibit neither B cells nor memory T cells effectively, and hence, fail to control chronic rejection. Therefore, investigating how B cells and T cells interact to promote long-lived immune responses that cause chronic allograft rejection is essential for developing novel therapies. Our preliminary data indicate that B cells provide important signals for alloreactive T cells to differentiate into long-lived memory lymphocytes. We hypothesize that B cells are a crucial link between the innate and adaptive immune response to a transplanted organ and promote generation of memory T cells that cause allograft rejection. The goal of this grant application is to investigate which B cell subsets are critical and how they are activated to provide help for T cell differentiation in the context of transplantation. The specific aims are: (a) to investigate which B cell subsets promote T cell differentiation to memory in alloimmunity;(b) to investigate how B cells are activated to promote T cell differentiation to memory in alloimmunity;and (c) to investigate if B cell depletion inhibits T cell differentiation to memory and prevents chronic allograft rejection. The specific aims will be accomplished using mixed bone marrow chimeras and transgenic mice to test the roles of B cell subsets, B cell innate activation and B cell depletion on development of T cell memory and chronic allograft rejection. The results of the proposed experiments will provide rationale for how and when to target B cells to prevent chronic allograft rejection and improve long-term survival of organ transplants. PUBLIC HEALTH RELEVANCE B cells and memory T cells cause acute and chronic allograft rejection that leads to loss of transplanted organs. We will investigate how B cells interact with T cells to generate long-lived (memory) immune responses that cause allograft rejection. Understanding these mechanisms will assist in the development of novel therapies that will target B cells and memory T cells to improve long-term survival of transplanted organs.